17a-(5{40 -substituted-5{40 -hydroxy-penta-1{40 , 3{40 -diynyl)-steroids

ABSTRACT

Compounds having sex hormonal activity consisting of steroid compounds processing a 17 Beta -oxygen function and being substituted in the 17 Alpha -position by a group of the structure   WHEREIN R1 is selected from the group consisting of carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 members and containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms; R2 is selected from the group consisting of hydrogen, carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 members and containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms; or R1 and R2 together with the carbon atom to which they are attached form an alicyclic ring. The compounds exhibit an unusual separation of oestrogenic and anti-fertility activities (in rats) compared with ethynyl oestradiol.

United States Patent 1 Burgess et al.

[ 1 Sept. 11, 1973 [73] Assignee: BDH Pharmaceuticals Limited,

Edinburgh, England [22] Filed: May 13, 1970 [21] Appl. No.: 37,035

Primary Examinerl-lenry A. French Attorney-Bacon and Thomas [57] ABSTRACT Compounds having sex hormonal activity consisting of steroid compounds processing a l7B-oxygen function and being substituted in the l7a-position by a group of the structure wherein R is selected from the group consisting of carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 members and containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms;

R is selected from the group consisting of hydrogen, carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 membersand containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms; or

R and R together with the carbon atom to which they are attached form an alicyclic ring.

The compounds exhibit an unusual separation of oestrogenic and anti-fertility activities (in rats) compared with ethynyl oestradiol.

7 Claims, N0 Drawings 1 l7A-( '-SUBSTlTUTED-5 '-HYDROXY-PENTA-l 3 -DlYNYL)-STEROIDS This invention is concerned with improvements in or relating to steroids having sex hormonal activity.

We have found that by modifying the structure of steroids having sex hormonal activity in the way hereinafterspecified, new compounds having modified sex hormonal properties may be produced. Such compounds exhibit, for example, oestrogenic or progestational properties, and are of value in human and veterinary medicine for the treatment of a wide range of conditions and defects of the reproductive system and for the limitation or enhancement of fertility.

According to the invention there are provided compounds having sex hormonal activity consisting of steroid compounds possessing a l7B-oxygen function and being substituted in the l7a-position by a group of the structure wherein R is a carbocyclic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having two-five carbon atoms or an alkyl group having one-five carbon atoms;

R is hydrogen, a carbocyclic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having two-five carbon atoms or an alkyl group having one-five carbon atoms; or

R and R together with the carbon atom to which they are attached form an alicyclic ring.

The term steroid is used herein to denote compounds having a nucleus derived from perhydro-l,2- cyclopentenophenanthrene. Since the compounds according to the invention are structurally related to compounds possessing sex hormonal activity they will ordinarily possess an oxygen function, e.g., hydroxy, methoxy or 0x0, at the 3-position; they will ordinarily possess unsaturation in ring A of an olefinic or aromatic character, but may be ring A-saturated; they will ordinarily possess a lower alkyl group at C and may or may not have a methyl group at C These functions are generally found in a variety of sex hormones to a greater or lesser extent although sex hormones devoid of, for example, a 3-oxygen function are known to exist.

The compounds according to the invention possess a Yin-oxygen function i.e., a l7B hydroxy group or an ester or ether group thereof, e.g., a lower alkoxy group or a lower alkanoyloxy group.

By sex hormonal activity" is meant activity of an oestrogenic, gestogenic or androgenic nature and includes such activity produced by naturally occurring steroids as well as by steroids not known to exist in .nature. The sex hormonal activity may be directly present in the compound or may be manifested in vivo by biological transformation of the compound. The term also includes activity manifested as anti-hormonal activity although the compounds in question possess some degree of normal hormonal activity e.g., a compound possessing residual oestrogenic activity may function as an ani-oestrogen.

R and R may, where their definitions permit, be the same or different.

When R or R is a carbocyclic aryl group this may be monoor bi-cyclic and when it is bicyclic the rings may be fused. R or R may thus be phenyl, lor 2- naphthyl or 0- or pbiphenylyl. One may use a carbocyclic aryl group in an unsubstituted form or such a group substituted by, for example, one or more fluorine, chlorine or bromine atoms, hydroxy groups, alkyl groups containing one-five carbon atmos, alkoxy groups containing one-five carbon atoms, or trifluoromethyl groups. Examples of such substituted carbocyclic aryl groups include p-tolyl, o-chlorophenyl, oand pmethoxyphenyl.

When R or R is an aralkyl group the aryl moiety or moieties may be a monoor bi-cyclic carbocylic group, substituted or unsubstituted, as explained above, and the alkyl moiety may contain one-five carbon atoms. Examples of such aralkyl groups include benzyl and phenethyl.

When R or R is a heterocyclic group it may be a 5-or 6-membered ring containing one or more hetero atoms selected from O, N and S. It may be aromatic or non-aromatic. Examples of such heterocyclic groups include 2- or 3-pyridyl and 2- or 3-thienyl.

When R or R is an alicyclic group it may be, for ex ample, cyclohexyl or adamantyl, while when R or R is alkenyl it may, for example, be vinyl, propenyl or isopropenyl.

When R or R is an alkyl group it may eg be a methyl, ethyl, propyl, isopropyl, nor secbutyl or npentyl group.

When R represents hydrogen R is preferably a carbocyclic aryl group, a heterocyclic group, an alicyclic group or an alkenyl group.

The compounds of the invention may be derived from any l7-keto or l7B-oxygen function-containing steroid compound having sex hormonal activity. In genera], but not exclusively, such compounds will contain unsaturation and/or substitutents in rings A and B.

Thus the compounds according to the invention may contain unsaturation as one or more A, A, A A, A A A, A A and A. For example, ring A may be aromatic or may contain A or A unsaturation. Again unsaturation may be present in or shared with rings A and B e.g. as A" or A'' or ring A may be aromatic and ring B may contain 1 or 2 double bonds.

Rings A and B may contain one or more substituents selected from acyloxy, alkoxy,alkyl and alkenyl (each containing up to 5 carbon atoms), halogeno, hydroxy and 0x0. One or more of these substitutents may be so chosen that they are metabolised in vivo to give unsaturation.

Ring C may be devoid of substituents or may, for example, contain an oxygen or halogen (i.e., chloro or bromo) function at C The compounds according to the invention include l9-nor compounds as well as IO-methyl compounds. They also include l3-methyl, -ethyl and -propyl compounds.

The compounds of the invention may, for example, belong to the androstane, l9-norandrostane (or oestrane), l8-methyloestrane or l8-ethyloestrane series.

Compounds of the invention which are of particular interest are those which exhibit oestrogenic and/or progestational activity; such compounds may be used in the control of fertility.

An important compound according to the invention is 17a-(5-hydroxy-5-methyl-l,3-hexadiynyl)-3- methyoxy-l,3,5( l) -oestratrien-l7B-ol which is a potent oestrogen many times more active than ethynyloestradiol as evidenced by vaginotrophic assay. This compound may be administered at a daily'dosage of from 1 to 10 .g in association with a progestational compound, e.g., megestrol acetate at a daily dosage of from 2 to mg, to women for 21 days during each menstrual cycle for the avoidance of fertility.

Compounds of this invention show an unusual separation of oestrogenic and anti-fertility activities in the experimental rat, in comparison with ethynyl oestradiol. The oestrogenic potency, determined in the conventional uterotrophic assay, is found to be small relative to the anti-fertility activity. The oestrogenic potency determined in the vaginotrophic assay, is significantly greater than in the uterotrophic assay and corresponds more closely to the anti-fertility activity. A sepration of potency between uterotrophic and vaginotrophic assays, relative to ethynyl oestradiol is quite unexpected.

A compound which, in the human, showed antifertility activity greater than corresponds to its overall hormonal activity offers advantages in oral contraceptive preparations in terms of decreased side-effects and increased safety, compared with ethynyl oestradiol, at present widely used in such preparations.

Important compounds according to the invention by virtue of the separation of their oestrogenic and antifertility activities include a. 17a-(5-hydroxy-5-phenyl-l ,3-pentadiynyl)-3- methoxy-l ,3 ,5( lO)-oestratrien 1 713-01;

b. l7a(5hydroxy-5-p-tolyl-l ,3-pentadiynyl)-3- methoxyl ,3,5( lO)-oestratrien -1 73-01;

c. l7a-[5-hydroxy-5-(2-napthyl)-l,3-pentadiynyl1-3- methoxy-l ,3,5() -oestratrien-l 73-01;

d. l7a-(5-hydroxy-5-o-chlorophenyl-1,2-pentadiynyl)- 3-methoxy-l ,3,5( l0)-oestratrien-l7)8-ol;

e. l7a-( S-hydroxy-S-cyclohexyl-l ,3-pentadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien-l7B-ol;

f. 17a-(5-hydroxy-p-biphenylyl-l ,3-pentadiynyl)-3- methoxyl ,3,5( l0)-oestratrien-17B-ol; and

2la-(5-hydroxy-5-methyl-l ,3-hexadiynyl)-3-methoxyl,3,5( l0)-oestratrien- 1 73-01 of which compounds (b), (d) and (f) show very significant separation in respect of these activities.

Compounds according to the invention exhibiting significant anti-fertility activity include .1713 -(5- hydroxy-l,3-hexadiynyl)-4-androsten17B-ol-3-one and l7a (5-hydroxy-5-methyll ,3-hexadiynyl)-4-oestrenl7fl-ol-3-one.

The compounds of the invention may be prepared by any suitable method. However, a further aspect of the invention provides a process for the preparation of said compounds which comprises reacting a mixture of an ethynyl compound R C 5 CH and a haloethylnyl compound R C E CBr wherein one of R, R" is a steroidal moiety to which the ethynyl or haloethynyl group is linked in the a-configuration at the l7-position and the other of R and R is the group wherein R and R have the above-defined meanings in a the presence of a cuprous salt, whilst maintaining said cuprous salt in the reduced state.

It is advantageous to employ a catalytic quantity of the cuprous salt, which is preferably a cuprous halide e.g., cuprous chloride, although other cuprous salts (e.g., the acetate) may be used. The two ethynyl reactants may be used in approximately equivalent proportions, or one may be in moderate excess. It is desirable to carry out the reacton in the presence of a base to assist the desired reaction and to take up hydrogen bromide. Where the base is a relatively strong organic base, e.g., a lower alkylamine such as ethylamine or triethylamine it may fulfil both functions; where it is a relatively weak organic base it should be used in association with an inorganic base, e.g., powdered sodium hydroxide or powdered calcium carbonate.

In order to maintain the cuprous salt in a reduced state, a reducing agent is desirably present in the reaction mixture. A preferred reducing agent is hydroxylamine or a salt thereof. It is advantageous to perform the reaction in an inert atmosphere, e.g., nitrogen.

Suitable temperatures for the reaction range between -l0 and 30C, preferably 5 to +5C.

The reaction is greatly assisted by a suitable reaction medium, which should be sufficiently polar to dissolve at least a minor amount of the cuprous salt of the ethynyl compound R -C E CH. It is not necessary for the reactants to be completely in solution but the reaction appears to take place in solution! It is highly desirable for the reaction medium to contain water. Suitable reaction media include lower alcohols (e.g. methanol or ethanol) or their mixtures with dimethylformamide, dimethylacetamide or dimethylsulphoxide, a proportion of water being present.

When the reaction is complete, a reagent, e.g., potassium cyanide, may be added to react with any residual acetylenic cuprous compound, and the steroid product may be removed by any convenient work-up procedure. For example the reaction mixture may be diluted with water and filtered or extracted with a solvent such as ether. Final purification may be by chromatography and/or recrystallisation. 1

When the steroid starting material contains an oxo group, such group may require protection from any reducing agent present in the reaction mixture. This may be achieved by converting the oxo group into, e.g., an enol ether, enamine, ketal, thioketal or oxime. Conveniently an excess of hydroxylamine may be used as reducing agent, whereby the oxo group is converted into an oxime. Thereafter the oxo group may be regenerated as desired. However, it may be found that an oxo group is not attacked to a sufficient extent to warrant protecting it.

Compounds according to the invention containing a 17B-hydroxy group may be prepared by reacting a 17- oxo steroid with a compound of the general formula wherein R and R are as defined above and M is Li, Na, K or Mg Hal (wherein Hal Cl, Br or l),and subsequently regenerating the desired derivative from the resulting complex. If M is Na, K or MgHal protection of the OH group of the acetylenic compound, e.g., by prior conversion into a tetrahydropyranyl ether, may be advantageous. The desired derivative is obtained by regeneration from the resulting complex by conventional procedures.

A still further method of preparing compounds according to the invention comprises treating a metal derivative (e.g., a Grignard reagent) of a l7q-(buta-l,3- diynyl) steroid compound with an aldehyde or ketone of the general formula RRCO, where R and R are as defined above.

'7 7 Where the compound obtained according to the in- The compositions according to the invention are intended for administration to both humans and animals. The term pharmaceutical as used herein to describe compositions and carriers means therefore that these are of use in both human and veterinary medicine.

The compositions are preferably in the form of dosage units and may be formulated for daily oral administration in such forms as tablets, capsules, sachets etc., either for taking directly or with a draught. Suppositories for rectal absorption may also be employed. Injection preparations may be formulated, preferably for more prolonged action, while implantation pellets may be formulated having the advantage of requiring very infrequent administration.

Conventional pharmaceutical excipients for solid preparations may for instance include sugar alcohols, sugars, starch, magnesium stearate, gelatine, polyethylene glycols and suitable colouring agents. Tablets may be coated for protection, colour distinction or elegance by conventional methods such as film coating or sugar or pearl coating. Suppositories may be prepared, using conventional bases such as glyco-gelatine, cocoabutter, or water-dispersible bases with a melting point above body temperature, such as polyglycols.

For injection purposes, preparations for intramuscular of subcutaneous administration may be prepared in conventional sterile oily, aqueous or emulsion bases, in solution and/or suspension. Vehicles preferably include physiologically acceptable vegetable oils, e.g., arachis oil, fractionated coconut oil; oily esters, e.g., isopropylmyristate; non-aqueous solvents, e.g., propylene glycol; aqueous vehicles such as sterile water or physiological saline; together with suitable formulatory agents such as suspending agents, e.g. aluminium stearate for oily materials, carboxymethyl cellulose for aqueous preparations; physiologically acceptable emulsifying agents,

e.g., Tween 8 l buffering agents for pH control, antioxidants, stabilising and solubilising agents. The injections may be formulated for immediate use, or as a dry powder for re-constitution before use with a separate vehicle. Unit injections required for prolonged action, e.g., 1 months duration, would naturally contain an increased quantity of active material.

Each dosage unit for daily administration to humans preferably contains 1 g to 5 mg active material according to the invention depending on the condition being treated and the potency of the compound.

Implantation pellets would in general contain a much higher dosage to cover prolonged activity for preferably several months. implants may be prepared aseptically from sterile material, by fusion or heavy compression, preferably without the addition of other substances.

For veterinary use in particular, long acting vaginal inserts such as tampons and pessaries, may be prepared in a conventional manner. The dosage required for animal treatment will of course, vary according to the size of the animal.

The progestational compounds of the invention may be employed as oral contraceptives, preferably either in daily doses of 0.1 mg to 5 mg on approx. 2l days in each menstrual cycle along or mixed with an oestrogen, e.g., ethynyl oestradiol 0.05 or 0.1 mg. Apart from their use as oral contraceptives, progestagens may be employed clinically in the following conditions; dysmenorrhoea, functional uterine bleeding, premenstrual tension, diagnosis of pregnancy, and endometriosis.

In order that the invention may be better understood, the following examples are given by way of illustration only.

Example 1 17a-(5-Hydroxy-5-phenyl-l ,3-pentadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien- 175-01 A solution of ethynyl-phenyl-carbinol (3.4 ml) in N,N-dimethyl-formamide (40 ml) was added to a stirred mixture of cuprous chloride (0.38 g), hydroxylamine hydrochloride (0.86 g), methanol (47 ml), N,N-dimethyl-formamide (80 ml), and aqueous ethylamine (9.7 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature. It was then cooled to 0C and l7a-bromoethynyl-3-methoxyl,3,5( l0)-oestratrienl -0] in N,N-dimethylformamide (87 ml) was added during 1 hour. The mixture was allowed to warm to room temperature, stirred for 2 hours, treated with potassium cyanide (L0 g) in water (l 1 ml), and poured into water (67 ml). The precipitate was collected and crystallised from a mixture of ether and light petroleum (b.p. 60 giving 17a- (S-hydroxy-S-phenyl-l,3-pentadiynyl)-3-methoxyl,3,5( l0)-oestratrien-l7[3-ol, m.p. l34 [a],,"-46 (C-l.2 in dioxan), A 287.5 nm (e, 2000), 278 nm (e, 2100), 246.5 nm (e, llOO).

Example 2 l7a-(5-Hydroxy-5-p-tolyll ,3-pentadiynyl)-3- methoxyl ,3 ,5( l0)'oestratrien- I 73-01 Sodium (23 g) was added to liquid ammonia (l litre) during passage of a stream of acetylene, to form the mono-sodium derivative of acetylene. p-Tolualdehyde (l20 g) in tetrahydrofuran (500 ml) was added and the mixture stirred under reflux, with continued passage of acetylene, for 3 hours. The ammonia was allowed to evaporate and the residue treated with water, acidified and extracted with ether. Distillation of the ether layer gave ethynyl-p-tolyl-carbinol b.p. 78/0.3mm.

A solution of ethynyl-p-tolyl-carbinol (3.89 g) in N,N-dimethylformamide (53 ml) was added to a stirred mixture of cuprous chloride (0.47 .g), hydroxylamine hydrochloride (1.03 g), methanol (57 ml), N,N-dimethylformamide (96 ml) and 70% aqueous ethylamine (12 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature. It was then cooled to C and a solution of l7a-bromoethynyl-3-methoxy- 1,3,S()-oestratrien-173-ol (8.0 g) in N,N,-dimethylformamide (104 ml) was added during 30 minutes; after a further 10 minutes at 0C, the mixture was allowed to warm to room temperature during 30 minutes. Potassium cyanide (1.32 g) in water (14.5 ml) was added and the mixture poured into ice/water. The precipitate was collected and crystallised from a mixture of benzene and light petroleum (b.p. 60 80), giving 17a-(5-hydroxy-5-p-tolyl-1,3-pentadiynyl)-3-methoxy- 1,3,5(l0)-oestratrien-l73-ol m.p. 154, [M m-436 (C-0.3 in dioxan), A 277.5 nm (e, 2173), 286.5 nm (e, 1968).

Example 3 a. Preparation of ethynyl-(2-naphthyl)-carbinol.

Ethyl magnesium bromide, prepared from ethyl bromide (30.0 g) and magnesium (6.8 g), in tetrahydrofuran (175 ml) was added during 2 hours to a saturated solution of acetylene-in tetrahydrofuran (150 ml). The mixture was stirred for 2 hours during continued passage of acetylene. Z-Naphthaldehyde- (25.0 g) was added and the mixture heated under reflux for 1 hour and allowed to cool. Saturated aqueous ammonium chloride solution (50 ml)v was then added to the mixture which was extracted with ether. Distillation of the ether layer gave ethynyl-2-naphthyl-carbino1 b.p. 148 l50/0.75 mm recrystallised from benzene, m.p. 61, b. 17a-[5-Hydroxy-5-(2-naphthyl)-l,3-pentadiynyl]-3- methoxy-1,3 ,5( 10)-oestratrien-1 73-01. I

A solution of ethynyl-(2-naphthyl)carbino1 (5.0 g) in N,N-dimethyl-formamide (53 ml) was added to a stirred mixture of cuprous chloride (0.47 g), hydroxylamine hydrochloride (1.03 g), methanol (57 ml), N,N-dimethyl-formamide (96 m1), and 70% aqueous ethylamine (12 ml) and the mixture was stirred for, 1 hour under nitrogen at room temperature. The mixture was cooled to 0C and a solution of l7a-bromoethynyl- 3-methoxy-1,3,5(10')-oestratrien-173-ol (8.0 g) in N,N-dimethylformamide (104 ml) was then added during 20 minutes. After a further 10 minutes at 0C, the mixture was allowed to warm to room temperature during 30 minutes. A solution of potassium cyanide (1.32 g) in water (14.5 ml) was then added and the mixture poured into ice/water. The precipitate was collected and crystallised from a mixture of benzene and light petroleum (b.p. 6O 80), giving 17a-[5-hydroxy-5-(2- naphthy1)- 1,3 -pentadiynyl]-3-methoxy-1,3,5(10)- oestratrien-l 73-01, m.p. 114 [ul -398 (C- 0.3 in dioxan) Mm 267.5 rim (6, 785 0). 247.75 nm (6, 49 00) 275.5 nm (e, 6650),-285.5 nm (e, 4850).

Example 4 1 7a-(5-Hydroxy-5-o-ch1orophenyl-1 ,3-pentadiynyl)-3- methoxy-1,3 ,5(10)-oestratrien-173-ol.

A solution of o-chlorophenyl-ethynyl-carbinol (4.75 g) in N,N-dimethylformamide (65 ml) was added to a stirred mixture of cuprous chloride (0.47 g), hydroxylamine hydrochloride (1.03 g), methanol (57 ml), N,N-dimethylformamide (96 ml) and 70% aqueous ethylamine (12 ml) under nitrogen at room temperature. The mixture was cooled to 0C and a solution of l7a-bromoethynyl-3-methoxy-l ,3,5( l0)-oestratrien- 173-01 (8.0 g) in N,N-dimethy1formamide (104 ml) was added during 25 minutes. After a further 10 minutes at 0C, the mixture was allowed to warm to room temperature during 45 minutes when a solution of potassium cyanide (1.32 g) in water (15 ml) was added and the mixture poured into ice/water. The precipitate was collected and crystallised from cyclohexane. Re-

moval of retained solvent in vacuo at 68 gave amorphous l70z-(5-hydroxy-5-o-chloro-phenyl-1,3- pentadiynyl)-3-methox y- ,3,5( 1 0)-oestratrien- 1 73-01 [M -3 91C, 0.3 in dioxan) Am, 24715 nin (e, 1400), 263.5 nm (e, 1600), 278 nm (e, 2200), 287.5 nm (e, 2000).

Example 5 17a-(5-Hydroxy-5,5-diphenyl-1,3-pentadiynyl)-3- methoxy-l ,3 ,5(10)-oestratrien-173-ol.

A solution of l7a-ethynyl-3-methoxy-1,3,5(10)- oestratrien-l73-ol (9.2 g) in N,N-dimethylformamide (50 ml) was added to a stirred mixture of cuprous chlroide (0.43 g), hydroxylamine hydrochloride (1.01 g), methanol (52 ml), N,N-dimethy1formamide (84 ml) and 70% aqueous ethylamine (13.6 ml) and the mixture was stirred under nitrogen at room temperature for 1 hour. A solution of l-bromo-3,3-diphenyl-lpropyn-3-ol (5.4 g) (W. Chodkiewicz, Annales de Chimie 2, 819 1957) in N,N-dimethylformamide (50 ml) was added during 1 hour. The mixture was stirred for 1% hours, treated with a solution of potassium cyanide (1.2 g) in water (50 ml), and poured into water. The precipitate was collected and purified by chromatography on silica gel, eluting with toluene/ethyl acetate. crystallisation from cyclohexane gave 17a-(5-hydroxy- 5,5-diphenyl-l,3-pentadiynyl)-3-methoxy-l,3,5(10)- oestratrien-l73-o1 containing cyclohexane of crystallisation, m.p. 96 97, [alb 35.7 (C-0.47 in dioxan), Mm1'287 nm (e, 1782 277 nm (e, 1927), 261.5 nm (e,

Example 6 a. Preparation 17a-bromoethynyl-63-methyl-5a-androstan-33, 5 ,1 73-triol.

Silver nitrate (15.0 g) was added to a solution of 17a-ethynyl-63-methyl-5a-androstan-BB, 5 ,1 73-triol (15.0 g) in ethanol (700 ml) and water (210 g). The mixture was stirred for 45 minutes, N- bromosuccinimide (15.0 g) was added, the mixture stirred for a further 5 minutes and poured into 5% aqueous sodium bicarbonate solution (3 litres). The precipitate was collected and purified from methylene chloride and acetone/light petroleum (b.p. 60-80"), giving 17a-bromoethynyl-6B-methyl-5a-androstan-33, 5,173-triol, m.p. 201, [al 52.3 (C- 0.25 in EtOH). b. 17a-(5-Hydroxy-5-pheny1-l ,3-pentadiynyl)-63- methyl-5a-androstan-33,5 ,173-triol A solution of ethynyl-phenyl-carbinol (4.0 ml) in N,N-dimethylformamide (40 ml) was added to a stirred mixture of cuprous chloride (0.45 g), hydroxylamine hydrochloride (1.00 g), methanol (55 m1), N,N-dimethyl-formamide ml) and 70% aqueous ethylamine (10.7 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature. The mixture was cooled to 0C and a solution of l7a-bromoethynyl- 63-methyl-5a-androstan-33,5,-173-trio1 (8.0 g) in N,N-dimethylformamide (l 10 ml) was added during 1 hour. The mixture was allowed to warm to room temperature, stirred for 2 hours, treated with a solution of potassium cyanide (1.2 g) in water (70 ml), and poured injo water (700 ml). The precipitate was collected and crystallised from ether/light petroleum and aqueous methanol, giving 17a-(5-hydroxy-5-phenyl-l ,3- pentadiynyl )6B-methyl-5a-androstan-3B,5 ,1 7B-triol, m.p. 175 [a]n -54.3 (C-0.5 in Et il Mar 299.5 nm (a, 331.7), 283 nm (s, 413.7), 259 nm (6, 867.5), 247 nm (e, 1039). Example 7 17a-[5-l-lydroxy-5-( l-naphthyl)-l ,3-pentadiynyl1-3- methoxy l,3,5( l)-oestratrien-l 73-01.

A solution of ethynyl-(l-naphthyl)-carbino1 (0.49 g) in N,N-dimethylformamide (5.0 ml) was added to a stirred mixture of cuprous chloride (0.047 g), hydroxylamine hydrochloride (0.103 g), methanol (5.7 ml), N,N-dimethyl-formamide (9.6 ml), and aqueous ethylamine (1.2 ml; 70%), and the mixture was stirred for 1 hour under nitrogen at room temperature. The mixture was cooled to 0C and a solution of 17abromoethynyl-3-methoxy-l,3,5(10)-oestratrien-17B-ol (0.80 g) in N,N-dimethylformamide (10.0 ml) was added during 10 minutes, and stirring continued at 0C for a further 10 minutes. A solution of potassium cyanide (0.13 g) in water (2.0 ml) was added and the mixture poured into water. The precipitate was collected and crystallised from cyclohexane giving 17a-[5- hydroxy5-( l-naphthyl)-1,3 ,pentadiynyll-B-methoxy- 1,3,5( l0)-oestratrien-1 718-01, containing cyclohexane of crystallisation, m.p. ill-defined, [a],,"- 33 (C-0.25 in dioxan) A 272 nm (e, 9700), 281.5 nm (6, 11900 M", 262.5 nm (e, 6200 286.5 nm (e, 9100). 292 nm (e, 7150).

Example 8 17a-(5Hydroxyl-S-cyclohexyl-1,3-pentadiynyl)-3- methoxy-1,3 ,5( )-oestratrien- 1 75-01.

A solution of ethynylcyclohexyl-carbinol (2.65 g) in N,N-dimethylformamide (30 ml) was added to a stirred mixture of cuprous chloride (0.28 g), hydroxylamine hydrochloride (0.64 g), methanol (35 ml), N,N-dimethylformamide (60 ml), and 70% aqueous ethylamine (7.2 ml) and the mixture was stirred under nitrogen for 1 hour at room temperature. The mixture was cooled to 0C and a solution of l7a-bromo-ethynyl-3- methoxy-l,3,5( l0)-oestratrien-l7B-ol (5.0 g) in N,N-dimethylformamide (70 m1) added during 80 minutes, when stirring was continued at 0C for 1% hours. A solution of potassium cyanide (0.74 g) in water (9 ml) was added and the mixture poured into water. The precipitate was collected and crystallised from cyclohexane giving 17a-(5-hydroxy-5-cyclohexyl-1 ,3- pentadiynyl)-3-methoxy- 1 ,3,5( 10)-oestratrien- 1 713-01, containing cyclohexane of crystallisation m.p. illdefined, i]'5 -36T3 (C, (Tim dioxin). 015; 261 nm (e, 831), 278 nm (e, 1911), 287.5 nm (e, 1804). Example 9 l7a-(5Hydroxy-S-o-methoxyphenyl-1,3-pentadiynyl)- 3-methoxy-l,3,5(10)-oestratrien-17B-ol A solution of ethynyl-o-methoxyphenyl-carbinol (3.37 g) in N,N-dimethylformamide (40 ml) was added to a stirred mixture of cuprous chloride (0.35 g), hydroxylamine hydrochloride (0.78 g), methanol (43 ml), N,N-dimethylformamide (73 m1) and 70% aqueous ethylamine (8.8 m1) and the mixture was stirred for 1 hour at room temperature, under nitrogen. The mixture was cooled to 0C, and a solution of 17a- 10 bromoethynyl-3-methoxy-l,3,5(10)-oestratrien-l7a-ol (6.08 g) in N,N-dimethylformamide (79 ml) was added during 80 minutes. The mixture was stirred for 2 hours at 0C and for 1 hour at room temperature. A solution of potassium cyanide (1.0 g) in water (1 1 ml) was added and the mixture poured into water. The precipitate was collected and purified by crystallisation from ether/cyclohexane giving l7a-(5-hydroxy-5-omethoxyphenyl-l,3-pentadiynyl-3methoxy-1,3,5( l0)- oestratrien-l7B-ol, containing cyclohexane of crystallisation, m.p. ill-defined, (a],, 22.5 (C- 0.4 in dioxan), Mm 220mm (6, 20500), 246.2 nm (e. 1950), 277 nm (e, 5400).

Example 10 a. Preparation of p-biphenylyl-ethynyl-carbinol.

Ethyl magnesium bormide, prepared from ethyl bromide (12.0 g) and magnesium (2.7 g) in tetrahydrofuran (50 ml) was added during 30 minutes to a saturated solution of acetylene in tetrahydrofuran (60 ml). The mixture was stirred for 1 hour during continued passage of acetylene. A solution of pphenylbenzaldehyde (8.5 g) in tetrahydrofuran (40 ml) was then added and the mixture heated under reflux for 1 hour and allowed to cool. Saturated aqueous ammonium chloride solution (25 ml) was then added and the mixture extracted with ether. The ether layer was washed, dried (Na- SO and freed from solvent at reduced pressure. Crystallisation of the residue from benzene/light petroleum (b.p. 60 80) gave p-biphenylylethynyl -carbinol. m.p. 1 17-8 Enmr 253.5 nm (6. 21517).

b. l7a-(S-Hydroxy-Sp-biphenylyl-1,3-pentadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien- 1 711-01.

A solution of p-biphenylyl-ethynyl-carbinol (5.8 g) in N,N-dimethylformamide ml) was added to a stirred mixture of cuprous chloride (0.47 g), hydroxylamine hydrochloride (1.03 g), methanol (57 ml), N,N-dimethylformamide (96 ml) and aqueous ethylamine (12 ml: and the mixture was stirred for 1 hour under nitrogen at room temperatureThe mixture was cooled to 0C and treated with a solution of 17a-bromethynyl- 3-methoxy-l,3,5(l0)-oestratrien-l7B-ol (8.0 g) N,N-dimethylformamide (104 ml) added during 25 minutes. The mixture was stirred at 0C for 10 minutes and for 1 hour while warming to room temperature, treated with a solution of potassium cyanide (1.2 g) in water (10 ml), and poured into water (2% litres). The precipitate was collected and crystallised from methylene chloride/light petroleum (b.p. 6080) giving 17 a-(5-hydroxy-5p-biphenylyl-1 ,3-pentadiynyl)-3- methoxy- 1,3,5(l0)-oestratrien-l7fi ol, m.p. 1 19, [a],, -39.8 (C, 0.33 in dioxan). Am": 220 nm (6. 18800), 232.5 nm (c, 14435), 255 nm (e, 24410). Example 11 l7a-(5Hydroxy-Sp-methoxyphenyl-l ,3-pentadiynyl)- 3-methoxy-1 ,3,5( 10)-oestratrien- 1 713-01.

A solution of ethynyl-p-methoxyphenyl-carbinol (0.443 g) in N,N-dimethylformamide (Sml) was added to a stirred mixture of cuprous chloride (0.047 g), hydroxylamine hydrochloride (0.103 g), methanol (5.7 m1), N,N-dimethylformamide (9.6 ml), and 70% aqueous ethylamine (1.2 ml) and the mixture was stirred for l5 to 20C and poured into water. The precipitate was collected and purified by chromatography on alumina, eluting with cyclohexane/ethyl acetate mixture. Crystallisation from cyclohexane gave l7a-(5-hydroxy- S-p-methoxyphenyl-l,3-pentadiynyl)-3-methoxy- 1,3,5( 10)-oestratrien-l 713-01, containing cyclohexane of crystallisation, m.p. 106C, [Glo -30.5 (C, 0.15 in dioxan); Km. 23 0 rim (a, 22700), 276 nm (e, 4600), 281 nm (e, 4200); M 286.5 nm (e, 3100).

Example 12 l7a-(5-l-lydroxy-5-methy1-l ,3-hexadiynyl)-3-methoxy- 1 ,3 ,5( 10 )-oestratrien- 1 73-01 A solution of 2-methyl-3-butyn-2-ol (3.00g) in N,N-dimethylformamide (50 ml) was added to a stirred mixture of cuprous chloride (0.43 g), hydroxylamine hydrochloride (1.01g), methanol (52 ml), N,N-dimethylformamide (84 m1), and 70% aqueous ethylamine (13.6 ml), and the mixture was stirred for 1 hour under nitrogen at room temperature. 17a-Bromoethyny1-3- methoxy-1,3,5(10)-oestratrien-17B-ol (8.00 g) in N,N-dimethylformamide was added during 1 hour. After a further 10 minutes, potassium cyanide (1.2 g) in water (15 ml) was added and the mixture was poured into water. The precipitate was collected a purified by crystallisation from a mixture of di-iso-propyl ether and light petroleum (60-80) and from aqueous methanol, giving 17a-(5-hydroxy-5-methyl-1,3-hexadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien-1 73-01, containing water of crystallisation, m.p. 104C, [ed 53.6 (c, 0.41 in 616x510, Am... 287.7 nm 2000), X 278.5 nm (e, 2200). Example 13 l7a-(5-Hydroxy-5-phenyl-1,3-pentadiyny1)-l,3,5(10)- oestratriene-3 ,17B-diol Silver nitrate (2.00 g) was added to a stirred solution of 3-acetoxy-l7a-ethyny1-1,3 ,5( l0)-oestratrien- 1 75-01 (2.00 g) in a mixture of ethanol (100 ml) and water (30 ml) and the mixture was stirred at room temperature for 35 minutes. N-Bromosuccinimide (2.00 g) was added and the mixture was stirred for 5 minutes and then poured into aqueous sodium bicarbonate solution. The precipitate was collected and'crystallised from squeous methanol giving 3-acetoxy-17a-bromoethynyl- 1,3,5()-oestratrien-l7B-ol, m.p. 176C, [01],, 13.5 (c, 0.68 in dioxan).

Ethynyl-phenyl-carbinol (5.0 ml) was added to a stirred mixture of cuprous chloride (0.60g), hydroxylamine hydrochloride (l.40 g), methanol (70 ml), N,N-dimethylformamide (120 ml) and 70% aqueous ethylamine (14.6 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature. It was then cooled to 0C and 3-acetoxy-l7a-bromoethynyl- 1,3,5(l0)-oestratrien-l7B-ol (10.00g) in N,N-dimethylformamide (130 ml) was added during 1 hour. The mixture was allowed to warm to room temperature, stirred for 2% hours, treated with acetic acid (20 ml) in water (150 ml) and poured into water (2.1). The precipitate was collected and purified by chromatography on an alumina column, eluting with a mixture of toluene and ether, giving l7a-(5-hydroxy-5-phenyll,3-pentadiynyl)- 1 ,3,5( 10)-oestratriene-3,l7fl-diol, m.p. 174-177C, [a 49.8 (c, 0.41 in dioxan), 1t 286 nm (e, 2150). Am", 281 nm (e. 2400).

Example 14 17a-(5-Hydroxy-5-methyl-l,3-hexadiynyl)-1,3,5(10- oestratriene-3 ,1 7fl -diol 2-Methyl-3-butyn-2-ol (0.60 g) in N,N-dimethylformamide (13 ml) was added to a stirred mixture of cuprous chloride (0.1 16 g), hydroxylamine hydrochloride (0.26 g), methanol (14 ml), N,N-dimethylformamide (24 ml) and aqueous ethylamine (3.0 ml) and the mixture was stirred at room temperature for 45 min. and then cooled to 0C. 3-Acetoxy-l 7a-bromoethynyl- 1,3,5(10)-oestratrien-l7B-ol (2.40 g) in N,N-dimethylformamide (25 ml) was added during 6 7 min. at 0C. After a further 5 min. potassium cyanide (0.33 g) in water (Sml) was added and the mixture was poured into water. The precipitate was collected and treated with potassium hydroxide (2.0 g) in ethanol (50 ml) and water 20 ml) at room temperature for 15 min. The solution was poured into water containing a slight excess of hydrochloric acid, and the precipitate was collected and dried. Purification by crystallisation from methylene chloride/ cyclohexane gave 17a-(5- hydroxy-S-methyl-l,3-hexadiynyl)-1,3,5(10)-oestratriene-3,l7B-diol, m.p. 140145C (ill-defined), A... 280 nm(, 2100) [MW-50.7" (C. 0.37 in dioxan), A 285 nm (e, 790), 285.3 nm (e, 1950). Example 15 l7a-(5-Hydroxy-l ,3-hexadiynyl)-3-methoxy- 1 ,3,5( l0)-oestratrien-1 73-01 55% Aqueous 1-butyn-3-ol (1.30 ml) was added to a stirred mixture of cuprous sulphite (0.10 g), hydroxylamine hydrochloride (0.15 g), methanol 12 ml), water (4 ml), and 70% aqueous ethylamine (3.4 m1) and the mixture was stirred at room temperature under nitrogen for 45 min. and then cooled to 0C. 17a- Bromethynyl-3-methoxy-1,3,5( 10)-oestratrien-l 73-01 (1.95 g) in methanol (50 ml) was added during 45 min. After a further 15 min. potassium cyanide (0.30 g) in water (3 ml) was added and the mixture was poured into water. The steroidal product was isolated by extraction with ether and purified by crystallisation from methylene chloride/cyclohexane, affording 17a-(5- hydroxy-l,3-hexadiynyl)-3-methoxy-l,3,5(10)-oestratrien-17B-ol, m.p. 129-1.34C, [01],, 40.8 (C, 0.37 in diOXan) Am nm (E, nm Example 16 3-Cyclopentyloxy-17oz-(5-hydroxy-5-methyl-l ,3- hexadiynyl)-l,3,5(10)-oestratrien-17B-ol 3-Cyc1opentyloxy-17a-ethynyl-1,3,5( l0)-oestratrien-17B-o1 (3.50g.) in'N,N-dimethylformamide (ml.) was added to a stirred mixture of cuprous chloride (0.- 25g.), hydroxylamine hydrochloride (0.50g.), methanol (3 lml.), N,N-dimethylformamide (50ml.) and 70% aqueous ethylamine (7.5 ml.), and the mixture was stirred under nitrogen while cooling to 0C., during 1 hour. 1-Bromo3-methyl-1-butyn-3-ol (1.50g.) in N,N-dimethylformamide (30ml.) was added during 1 hour. The mixture was allowed to warm to room temperature during 1 hour, and potassium cyanide (1.5g.) in water (20ml.) was added. The mixture was added to water (1 litre) and the steroidal product collected by filtration, dried, and purified by crystallisation from aqueous methanol, giving 3-cyclopentyloxy-17a-(5- hydroxy-S-methyl-l,3-hexadiynyl)-1,3,5(10)-oestratri- ,3-hexadiynyl)-4-andros- The 3oxime of l7a-ethynyl-4-androsten-173-01- 3-one (17.00g.) in N,N-dimethy1formamide (350ml.) was added to a stirred mixture of cuprous chloride (1.- 25g.), hydroxylamine hydrochloride (2.50g.), methanol (156ml), N,N-dimethylformamide (250ml.) and 70% aqueous ethylamine (37.5ml.), and the mixture was stirred under nitrogen while cooling to C. during 1 hour. 1-Bromo-3-methyl-1-butyn-3-ol (7.50g.) in N,N-dimethylformamide (l50ml.) was added during 1 hour. The mixture was allowed to warm to room temperature during 1 hour and potassium cyanide (0.75g.) in water (l0ml.) added. The mixture was poured into water (4 litres) and the steroidal product collected by filtration. Crystallisation from aqueous methanol gave the oxime m.p. 240-241C.

A mixture of the oxime (8.00g.), glacial acetic acid (40ml.), pyruvic acid (6.24g.), sodium acetate (3.04g.) and water (16 ml.) was refluxed for four hours, and poured into water (650ml.). The steroidal product was collected by filtration and purified by crystallisation from aqueous methanol, giving 17a-(5-hydroxy-5- methyl-l ,3-hexadiyny1)-4-androsten-173-o1-3-one, mp. 233C, [015 -34 (cfilfitin dioxan), Xmriz 240 nm (c, 15728).

Example 18 l7a-(5-Hydroxy-5 -methyl- 1 ,3-hexadiynyl )-4-oestren- 173-o1-3-0ne 17a-Ethynyl-3-methoxy-3,5-oestradien-173-01 l 3.- 6g.) in N,N-dimethylformamide (340ml.) was added to a stirred mixture of cuprous chloride (l.13g.), hydroxylamine hydrochloride (3.40g.), methanol (142m1.), N,N-dimethylformamide (226.5ml.) and 70% aqueous ethylamine (34ml.) and the mixture was stirred at room temperature under nitrogen for min. and then cooled to 0C. l-Bromo-3-methyl-l-butyn-3-ol (6.80g.) in N,N-dimethy1formamide (l36ml.) was added during 1 hour. The mixture was allowed to warm to room temperature, stirred for 75 min., and poured into water (4.5 litres). The steroidal product was isolated by extraction with ether and treated in refluxing methanol (800 ml.) with p-toluenesulphonic acid (2.08g.) and water (5.5ml.) for 10 min. The methanolic solution was poured into water and the steroidal product collected by filtration, dried, and purified by chromatography on alumina, eluting with toluene/ether, and by crystallisation from cyclohexane/ether, giving l7a-(5-hydroxy-5- methyl-l,3-hexadiynyl)-4-oestren-173-o1-3-one, m.p. l3l-143C., [a] D 80.5 (c, 0.58 in dioxan), A, 239.5 nm (s, 148 00).

Example 19 l7a-( S-Hydroxy-S-methyl-l ,3-hexadiyny1)-5- androstene-33,1 73-diol 17a-Ethynyl-5-androstene-33,l73-diol (7.00g.) in N,N-dirnethylformamide (150m1.) was added to a stirred mixture of cuprous chloride (0.50g.), hydroxylamine hydrochloride (l.00g.),' methanol (6.25ml.), N,N-dimethylformamide (l00ml.) and 70% aqueous ethylamine m1.), and the mixture was stirred under nitrogen while cooling to 0C. during 30 minutes. l-Bromo-3-methyl-l-butyn-3-o1 (3.00g.) in N,N-dimethylformamide (60m1.) was added during 1 hour. The mixture was allowed to warm to room temperature during 1 hour, and potassium cyanide (3.0g.) in water (40 ml.) was added. The mixture was poured into water (2 litres) and the steroidal product was collected by filtration, dried, and purified by crystallisation from aqueous methanol and from ether/light petroleum giving 17a- 14 (5-hydroxy-5-methy1-l ,3-hexadiynyl)-5-androstene- 33,173-diol, mp 209C. [a],,=- (c, 0.54 in dioxan).

We claim:

1. A compound having sex hormonal activity selected from the group cnsisting of steroid compounds of the androstane of oestrane series possessing a 173- hydroxy, lower alkoxy or lower alkanoyloxy group and being substituted in the 17oz-position by a group of the structure wherein R is selected from the group consisting of carbocyclic aryl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl, 2- thienyl, 3-thieny1, alicyclic, and alkenyl having 2-5 carbon atoms;

R is selected from the group consisting of hydrogen,

carbocyclic aryl, benzyl, phenethyl, 2-pyridyl, 3- pyridyl, Z-thienyl, 3-thienyl, alicyclic, alkenyl having two-five carbon atoms and alkyl having 1-5 carbon atoms; or

R and R together with the carbon atoms to which they are attached form an alicyclic ring.

2. A compound as defined in claim 1 having an oxygen function at the 3-position.

3. A compound as defined in claim 1 possessing olefinic or aromatic unsatruation in ring A.

4. A compound as defined in claim 1 wherein said 173-oxygen function is a hydroxy group.

5. A compound as defined in claim 1 wherein R or R is selected from the group consisting of phenyl, 1- naphthyl, 2-naphthyl, o-biphenylyl and p-biphenylyl groups, and groups of this character substituted by at least one member selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C -C alkyl, C,-C alkoxy and trifluoromethyl groups.

6. A compound as defined in claim 1 wherein R is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl and isopropenyl; and

R is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl, isopropenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and n-pentyl.

7. A compound as defined in claim 1 selected from the group consisting of l7a-(5-hydroxy-5-pehnyl-l ,3-pentadiynyl)-3- methoxyl ,3,5( lO)-oestratrien-173-o1;

l7a-( S-hydroxy-S-p-tolyl-l ,3-pentadiynyl)-3- methoxy-1,3,5( l0)-oestratrien-l73-ol;

l7a-[ 5-hydroxy-5-( 2-naphthyl)-l ,3-pentadiynyl1-3- methoxy- 1 ,3 ,5( l0)-oestratrien-l73-o1;

l7a-( 5-hydroxy-5-o-chloropheny1-l ,3-pentadiynyl)- 3-methoxy-l ,3-5( l0)-oestratrien-l 73-01;

l7a-(5-hydroxy-5 ,S-diphenyl-l ,3-pentadiynyl)-3 methoxy-1,3,5( 10)-oestratrien- 1 73-01;

l7a-(S-hydroxy-5-phenyl-l ,3-pentadiyny1)-63- methyl-5a-androstan-3 3,5 ,1 73-triol;

17a-[5-hydroxy-5-(1-naphthyl)-l,3-pentadiyny11-3- methoxyl ,3,5( 10)-oestratrienl 73-01;

17a-( S-hydroxy-S-cyclohexyll ,3-pentadiynyl )-3- methoxy-l ,3,5( 10)-oestratrien- 1 73-01; 

2. A compound as defined in claim 1 having an oxygen function at the 3-position.
 3. A compound as defined in claim 1 possessing olefinic or aromatic unsatruation in ring A.
 4. A compound as defined in claim 1 wherein said 17 Beta -oxygen function is a hydroxy group.
 5. A compound as defined in claim 1 wherein R1 or R2 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, o-biphenylyl and p-biphenylyl groups, and groups of this character substituted by at least one member selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and trifluoromethyl groups.
 6. A compound as defined in claim 1 wherein R1 is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl and isopropenyl; and R2 is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl, isopropenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and n-pentyl.
 7. A compound as defined in claim 1 selected from the group consisting of 17 Alpha -(5-hydroxy-5-pehnyl-1,3-pentadiynyl)-3-methoxy-1,3, 5(10)-oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5-p-tolyl-1,3-pentadiynyl)-3-methoxy-1,3, 5(10)-oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5-(2-naphthyl)-1,3-pentadiynyl)-3-methoxy-1,3,5(10)-oestratrien -17 Beta -ol; 17 Alpha -(5-hydroxy-5-o-chlorophenyl-1,3-pentadiynyl)-3-methoxy-1,3-5(10) -oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5,5-diphenyl-1,3-pentadiynyl)-3-methoxy-1, 3,5(10)-oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5-phenyl-1,3-pentadiynyl)-6 Beta -methyl-5 Alpha -androstan-3 Beta ,5,17 Beta -triol; 17 Alpha -(5-hydroxy-5-(1-naphthyl)-1,3-pentadiynyl)-3-methoxy-1,3,5(10)-oestratrien -17 Beta -ol; 17 Alpha -(5-hydroxy-5-cyclohexyl-1,3-pentadiynyl)-3-methoxy-1, 3,5(10)-oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5-o-methoxyphenyl-1,3-pentadiynyl)-3-methoxy-1,3,5(10) -oestratrien-17 Beta -ol; 17 Alpha -(5-hydroxy-5-p-biphenylyl-1,3-pentadiynyl)-3-methoxy-1,3,5(10)-oestratrien -17 Beta -ol; 17 Alpha -(5-hydroxy-5-p-methoxyphenyl-1,3-pentadiynyl)-3-methoxy-1,3,5(10) -oestratrien-17 Beta -ol; and 17 Alpha -(5-hydroxy-5-phenyl-1,3-pentadiynyl-1,3,5(10)-oestratrien-3,17 Beta -diol. 